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INTRODUCTION: The monoclonal antibody therapies bamlanivimab (BAM) + etesevimab (ETE) received emergency use authorization (EUA) from the US Food and Drug Administration (February 9, 2021) for treatment of mild-to-moderate COVID-19. The EUA of BAM + ETE was revoked (December 14, 2023) due to the high prevalence of BAM + ETE-resistant variants of SARS-CoV-2. Efficacy and safety of 700/1400 mg and 2800/2800 mg BAM + ETE are well established and published; however, efficacy and safety of 350/700 mg BAM + ETE have not been disclosed to date. METHODS: This portion of phase 3, BLAZE-1 trial (J2X-MC-PYAB) enrolled patients (between June 17, 2020 and April 9, 2021) with mild-to-moderate COVID-19 within 3 days of laboratory diagnosis of SARS-CoV-2 infection. In total, 354 patients with at least one risk factor for severe COVID-19 were enrolled, randomized (2:3), and infused with placebo (N = 141) or 350/700 mg BAM + ETE (N = 213), over ~ 8 min. Primary endpoint was to assess proportion of patients with persistently high SARS-CoV-2 viral load (PHVL) (log viral load > 5.27) 7 days after infusion. RESULTS: Patients were aged (mean) 53 years, 49.7% female, and 82.7% White. Seven days after drug infusion, 10.8% (95% confidence interval: 6.6, 15.0; p < 0.001) of BAM + ETE-treated patients and 34.8% (26.9, 42.6) of placebo-treated patients had PHVL, and the viral load change from baseline (least square mean [standard error]) was - 3.50 (0.15; p < 0.001) in BAM + ETE-treated patients versus - 2.51 (0.19) in placebo-treated patients. The majority of treatment-emergent adverse events were considered mild or moderate in severity (BAM + ETE: 6.6%; placebo: 14.2%). No deaths were reported. CONCLUSIONS: Consistent with previous studies, patients treated with BAM + ETE (350/700 mg) had a significantly lower proportion of PHVL and greater reduction in viral load compared with placebo. The overall safety profile is consistent with higher doses of BAM + ETE. Infusions of over ~ 8 min did not result in meaningful increase in incidence of TEAEs compared to higher doses of BAM + ETE administered over 30-60 min. TRIAL REGISTRATION: Clinical trial.gov identifier, NCT04427501.

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This paper highlights how micro-CT was used to assist in the investigation of hybrid firearms constructed using a mixture of plastic and metal components, as a complementary technique to the physical examination performed by firearms experts. In recent years, there has been an increase in the complexity and sophistication of 3D printed and hybrid firearm designs. This was also the case in the investigation presented herein, with the firearms seized demonstrating a step change in the threat level they pose through their complexity. Thus, we describe how data produced from micro-CT scans was used to help firearms experts study the viability and mechanics of two hybrid weapons prior to dismantling and test-firing. This process aided experts in determining whether components were 3D printed or manufactured through other means, whilst ensuring that a digital record (digital twin) was retained in case evidence was damaged during testing. Finally, we show how the data was presented visually through animations and as evidence in court. This proved to be imperative when communicating to the judge, jury, and wider investigating teams, the complex multiple components and mechanisms within the firearms.

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Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

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The Eastern Corn Belt (ECB) Long-Term Agroecosystem Research (LTAR) network site is one of the most agriculturally productive areas in the United States; however, nutrient and sediment losses from this region directly contribute to water quality impairment in both the Gulf of Mexico and Lake Erie. One of the largest challenges facing agricultural production in the ECB is water management, especially under a changing climate. Shifting precipitation patterns in combination with evolving infrastructure (i.e., tile drainage, irrigation) and management (i.e., crops planted; 4R nutrient management: source, timing, rate, and placement) in response to changing climate are likely to alter water quantity and quality and agricultural productivity. Through plot- and field-scale research, the ECB Common Experiment (CE) is focused on crop, soil, and water management to support sustainable agricultural intensification, with the goal of maximizing profitability, minimizing agriculture's environmental footprint, and enhancing ecosystem services. At both spatial scales, the CE aims to examine differences in water quantity and quality between the primary prevailing crop production system in the ECB (i.e., corn [Zea mays L.]-soybean [Glycine max L.] rotation, tillage prior to corn planting, free drainage, and fertility management consistent with tri-state recommendations) and an alternative system (e.g., adding small grains into the crop rotation, cover crops, limited phosphorus fertilizer, and drainage water management). Aligning producer and stakeholders needs with research objectives and long-term data collection, the ECB CE will tackle both ongoing and newly emerging research priorities and explore the effectiveness of conservation strategies to decrease nutrient and sediment losses from agricultural land.

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INTRODUCTION: Many physicians administer steroids after radiofrequency ablation (RFA) to mitigate postprocedural inflammation and decrease postprocedural pain. However, robust evidence supporting the benefits of steroids after RFA is lacking and steroids have risks. METHODS: This study was a single-center, prospective, observational study designed to assess whether RFA alone is inferior to RFA with steroids for postprocedure pain. Eligible patients were at least 18 years of age and scheduled to undergo cervical or lumbar RFA. The primary outcome measure was the average pain score on the numeric rating scale (NRS) 7 days after the RFA. The secondary outcome measures included anxiety, depression and physical function, measured via the Patient-Reported Outcomes Measurement Information System short forms. All outcome measures were completed prior to the procedure and at 7 and 60 days postprocedure. RESULTS: Out of the 365 participants who completed baseline assessments, 175 received steroids and 190 did not receive steroids. The pain intensity at 7 days postprocedure was similar between the steroid and non-steroid groups (mean difference (steroid-non-steroid): -0.23). The 95% CI of the estimate (-0.76 to 0.30) was within the prespecified non-inferiority margin of 1.5 NRS points. Similar results were obtained for pain at 60 days (mean difference: 0.09; 95% CI -0.48 to 0.65). No significant differences between groups were observed for anxiety, depression or physical function at either 7 or 60 days. CONCLUSION: This study suggests that the addition of steroids to the RFA procedure does not provide added benefits and is therefore not worth the additional risks that they pose.

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Post-pandemic school absence is an increasing concern for governments worldwide. Absence is associated with poor academic outcomes and long-term illness (physical and mental). Absenteeism increases the risk of financial difficulties in adulthood and involvement in the criminal justice system. We hypothesized that early childhood problems might be an antecedent of absenteeism. We tested this hypothesis by investigating the pre-pandemic association between school readiness and persistent absenteeism using a population-linked dataset. Analyses included 62,598 children aged 5-13 years from the Connected Bradford database (spanning academic years 2012/13 to 2019/20). Special educational needs status, English as an Additional Language status, socioeconomic status, sex and ethnicity were covariates significantly associated with persistent absenteeism. Children who were not 'school ready' had increased odds of being persistently absent later in their education journey after controlling for these covariates. School readiness was associated with even greater odds of being persistently absent over two or more years. These findings show (i) the seeds of absenteeism are sown early in childhood; (ii) absenteeism shows the hallmark of structural inequities; and (iii) the potential of 'school readiness' measures to identify children at risk of long-term disengagement from the education system.

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INTRODUCTION: Current upper limb assessment methods in MS rely on measuring duration in tasks like the nine-hole peg test (9HPT). Kinematic techniques may provide a more useful measure of functional change in clinical and research practice. The aim of this study was to assess upper limb function prospectively in people with progressive MS using a kinematic 3D motion capture system and compare with current measures. METHODS: 42 people with progressive MS (PwPMS) and 15 healthy controls reached-and-grasped different objects whilst recorded by a kinematic assessment system. 9HPT, Expanded Disability Status Scale (EDSS), and patient reported outcome measures (PROs) were collected. All measures were taken at baseline for PwPMS and controls, and again at six months for PwPMS. RESULTS: Relative to controls, PwPMS had significantly longer reaction (0.11 s, p < 0.05) and reach (0.25 s, p < 0.05) times. PwPMS took longer to pick-up (0.34 s, p < 0.05), move (0.14 s, p < 0.05), and place (0.18 s, p < 0.05) objects. PwPMS had lower peak velocities when reaching (7.4 cm/s, p < 0.05) and moving (7.3 cm/s, p < 0.05) objects. Kinematic assessment demonstrated consistent differences between PwPMS with mild and severe upper limb dysfunction as defined by PROs, which were not captured by 9HPT or EDSS in this group. PwPMS demonstrated altered grip apertures profiles, as measured by their ability to complete individual parts of the reach and grasp task, between the baseline and follow-up timepoints. CONCLUSIONS: We have created and tested a novel upper limb function assessment tool which has detected changes and characteristics in hand function, not currently captured by the EDSS and 9HPT.

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The HIV-1 nucleocapsid protein (NC) is a multifunctional viral protein necessary for HIV-1 replication. Recent studies have demonstrated that reverse transcription (RT) completes in the intact viral capsid, and the timing of RT and uncoating are correlated. How the small viral core stably contains the ~10 kbp double stranded (ds) DNA product of RT, and the role of NC in this process, are not well understood. We showed previously that NC binds and saturates dsDNA in a non-specific electrostatic binding mode that triggers uniform DNA self-attraction, condensing dsDNA into a tight globule against extending forces up to 10 pN. In this study, we use optical tweezers and atomic force microscopy to characterize the role of NC's basic residues in dsDNA condensation. Basic residue mutations of NC lead to defective interaction with the dsDNA substrate, with the constant force plateau condensation observed with wild-type (WT) NC missing or diminished. These results suggest that NC's high positive charge is essential to its dsDNA condensing activity, and electrostatic interactions involving NC's basic residues are responsible in large part for the conformation, size, and stability of the dsDNA-protein complex inside the viral core. We observe DNA re-solubilization and charge reversal in the presence of excess NC, consistent with the electrostatic nature of NC-induced DNA condensation. Previous studies of HIV-1 replication in the presence of the same cationic residue mutations in NC showed significant defects in both single- and multiple-round viral infectivity. Although NC participates in many stages of viral replication, our results are consistent with the hypothesis that cationic residue mutations inhibit genomic DNA condensation, resulting in increased premature capsid uncoating and contributing to viral replication defects.

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OBJECTIVE: Major depressive disorder (MDD) is linked to a 61% increased risk of emergency department (ED) visits and frequent ED usage. Collaborative care management (CoCM) models target MDD treatment in primary care, but how best to prioritize patients for CoCM to prevent frequent ED utilization remains unclear. This study aimed to develop and validate a risk identification model to proactively detect patients with MDD in CoCM at high risk of frequent (≥ 3) ED visits. STUDY DESIGN: This retrospective cohort study utilized electronic health records from Mayo Clinic's primary care system to develop and validate a machine learning-based risk identification model. The model predicts the likelihood of frequent ED visits among patients with MDD within a 12-month period. METHODS: Data were collected from Mayo Clinic's primary care system between May 1, 2006, and December 19, 2018. Risk identification models were developed and validated using machine learning classifiers to estimate frequent ED visit risks over 12 months. The Shapley Additive Explanations model identified variables driving frequent ED visits. RESULTS: The patient population had a mean (SD) age of 39.78 (16.66) years, with 30.3% being male and 6.1% experiencing frequent ED visits. The best-performing algorithm (elastic-net logistic regression) achieved an area under the curve of 0.79 (95% CI, 0.74-0.84), a sensitivity of 0.71 (95% CI, 0.57-0.82), and a specificity of 0.76 (95% CI, 0.64-0.85) in the development data set. In the validation data set, the best-performing algorithm (random forest) achieved an area under the curve of 0.79, a sensitivity of 0.83, and a specificity of 0.61. Significant variables included male gender, prior frequent ED visits, high Patient Health Questionnaire-9 score, low education level, unemployment, and use of multiple medications. CONCLUSIONS: The risk identification model has potential for clinical application in triaging primary care patients with MDD in CoCM, aiming to reduce future ED utilization.

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Background: Adolescence and transition into adulthood are periods shaping life-long mental health, cardiometabolic risk, and inequalities. However, they are poorly studied and understood. By extending and expanding the Born in Bradford (BiB) cohort study through this period using innovative, co-produced approaches to collect and analyse data, we aim to understand better the interplay of factors that influence health and wellbeing, and inform/evaluate interventions to improve them and reduce inequalities. Protocol: BiB Age of Wonder (AoW) is a large, whole city cohort that will capture the contemporary lived experience amongst multi-ethnic adolescents progressing into young adulthood. We will collect repeated data from existing BiB participants and their peers (N~30,000 adolescents). The protocol for the first phase of the quantitative methods, involving survey measurements and health assessments in mainstream secondary schools is described here. We describe the co-production behind these methods, and lessons learned from the first year of data collection.

Born in Bradford have been following the health and wellbeing of over 13,000 Bradford children since they were born. This group of children are now in their teenage years ­ a time that is crucial for their future mental and physical health. Age of Wonder aims to capture this journey through adolescence and early adulthood with up to 30,000 young people in Bradford over 7 years. In the first phase of this project, data collection is taking part in secondary schools in Bradford. This protocol describes how this data collection is currently being carried out in the schools. Young people aged 12-15 are being asked to complete questionnaires, covering topics such as mental and physical health. These topics have been designed with groups of young people, schools and other partners, to make sure we are capturing data on the things most important to young people. Those in Year 9 (13-14 years old), are also asked to take part in physical health measurements such as height, weight, blood pressure and a blood sample, as well as computer-based assessments of cognition (memory), movement and language. There have been a number of lessons learned from the first full year of data collection, such as how to make the research as easy as possible for schools to take part in when they have so many competing demands on their time.

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Child abuse is a serious concern that can cause the death of a child. In such cases the medico-legal evidence is often pivotal but complex, drawing across multiple medical disciplines and techniques. One key specialism is histopathology, which is considered the gold standard for estimating the age of individual fractures. Another is micro-CT imaging, which can visualise the location of trauma across the body. This case report demonstrates how micro-CT was used to contextualise the histological evidence in the Criminal Justice Proceedings of a fatal child abuse case. This was achieved by overlaying the aged fracture evidence from histopathology onto the visuals rendered from micro-CT imaging. The case was a suspected child abuse of a deceased 1-month old infant who was reported unresponsive by their parents. The child was taken to hospital where they were pronounced dead. Suspicion was raised and post-mortem imaging confirmed head trauma and rib fractures, and the case was escalated for a forensic investigation. This case report details how the micro-CT imaging was merged with the gold standard of histopathology for visualisation of trauma, and how the court presentation was planned alongside Senior Investigating Officers and various medical experts. The presentation was used in court by the histopathologist to present the evidence. The resulting presentation provided additional clarity to jury members regarding the location, severity, frequency, and timings of the injuries. From the perspective of the investigating police force, the resulting presentation was crucial in ensuring understanding of the medico-legal evidence of how the infant died. The prosecuting lawyer noted that combining the histological and micro-CT evidence in this way allowed the evidence to be presented in a sensitive, clear, and impactful manner.

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There are numerous crime scene investigation applications of 3D scanning that have been previously documented. This paper documents the application of a 3D point cloud in the presentation of Bloodstain Pattern Analysis evidence to mock jurors. 150 mock jurors viewed a presentation of Bloodstain Pattern Analysis evidence from a murder trial in the UK. After viewing the evidence, the participants were tested on their knowledge of the evidence and repeated the test again 2 weeks later; to simulate criminal trial conditions; whereby there is a time lapse between the initial viewing of evidential material and deliberation. This paper found that the mock jurors who additionally viewed a 3D flythrough of a point cloud of the crime scene, better retained knowledge of the evidence over time, reported a greater ability to visualise the crime scene and had higher levels of interest in the evidence. Crucially, the 3D flythrough group did not report different levels of confidence in the accuracy of their memories of the evidence, nor different levels of emotional arousal to the group that viewed the evidence without the 3D presentation. Together, these findings suggest that 3D scanning of crime scenes, and the resultant point cloud's presentation to jurors, could add further value to the justice system when spatial information, such as Bloodstain Pattern Analysis evidence, is presented.

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BACKGROUND: Not being in employment, education, or training (NEET) is associated with poor health (physical and mental) and social exclusion. We investigated whether England's statutory school readiness measure conducted at 4-5 years provides a risk signal for NEET in late adolescence. METHODS: We identified 8,118 individuals with school readiness measures at 4-5 years and NEET records at 16-17 years using Connected Bradford, a bank of linked routinely collected datasets. Children were categorised as 'school ready' if they reached a 'Good Level of Development' on the Early Years Foundation Stage Profile. We used probit regression and structural equation modelling to investigate the relationship between school readiness and NEET status and whether it primarily relates to academic attainment. RESULTS: School readiness was significantly associated with NEET status. A larger proportion of young people who were not school ready were later NEET (11%) compared to those who were school ready (4%). Most of this effect was attributable to shared relationships with academic attainment, but there was also a direct effect. Measures of deprivation and Special Educational Needs were also strong predictors of NEET status. CONCLUSIONS: NEET risk factors occur early in life. School readiness measures could be used as early indicators of risk, with interventions targeted to prevent the long-term physical and mental health problems associated with NEET, especially in disadvantaged areas. Primary schools are therefore well placed to be public health partners in early intervention strategies.

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Human sensorimotor decision making has a tendency to get 'stuck in a rut', being biased towards selecting a previously implemented action structure (hysteresis). Existing explanations propose this is the consequence of an agent efficiently modifying an existing plan, rather than creating a new plan from scratch. Instead, we propose that hysteresis is an emergent property of a system learning from the consequences of its actions. To examine this, 152 participants moved a cursor to a target on a tablet device while avoiding an obstacle. Hysteresis was observed when the obstacle moved sequentially across the screen between trials, whereby the participant continued moving around the same side of the obstacle despite it now requiring a larger movement than the alternative. Two further experiments (n = 20) showed an attenuation when time and resource constraints were eased. We created a simple computational model capturing probabilistic estimate updating that showed the same patterns of results. This provides, to our knowledge, the first computational demonstration of how sensorimotor decision making can get 'stuck in a rut' through the updating of the probability estimates associated with actions.

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HIV-1 cores, which contain the viral genome and replication machinery, must disassemble (uncoat) during viral replication. However, the viral and host factors that trigger uncoating remain unidentified. Recent studies show that infectious cores enter the nucleus and uncoat near the site of integration. Here, we show that efficient uncoating of nuclear cores requires synthesis of a double-stranded DNA (dsDNA) genome >3.5 kb and that the efficiency of uncoating correlates with genome size. Core disruption by capsid inhibitors releases viral DNA, some of which integrates. However, most of the viral DNA is degraded, indicating that the intact core safeguards viral DNA. Atomic force microscopy and core content estimation reveal that synthesis of full-length genomic dsDNA induces substantial internal strain on the core to promote uncoating. We conclude that HIV-1 cores protect viral DNA from degradation by host factors and that synthesis of long double-stranded reverse transcription products is required to trigger efficient HIV-1 uncoating.

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Lithium-ion battery electrodes are typically manufactured via slurry casting, which involves mixing active material particles, conductive carbon, and a polymeric binder in a solvent, followed by casting and drying the coating on current collectors (Al or Cu). These electrodes are functional but still limited in terms of pore network percolation, electronic connectivity, and mechanical stability, leading to poor electron/ion conductivities and mechanical integrity upon cycling, which result in battery degradation. To address this, we fabricate trichome-like carbon-iron fabrics via a combination of electrospinning and pyrolysis. Compared with slurry cast Fe2O3 and graphite-based electrodes, the carbon-iron fabric (CMF) electrode provides enhanced high-rate capacity (10C and above) and stability, for both half cell and full cell testing (the latter with a standard lithium nickel manganese oxide (LNMO) cathode). Further, the CMFs are free-standing and lightweight; therefore, future investigation may include scaling this as an anode material for pouch cells and 18,650 cylindrical batteries.

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The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called 'FLip' mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.

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Bacteriophage T4 gene 32 protein (gp32) is a single-stranded DNA (ssDNA) binding protein essential for DNA replication. gp32 forms stable protein filaments on ssDNA through cooperative interactions between its core and N-terminal domain. gp32's C-terminal domain (CTD) is believed to primarily help coordinate DNA replication via direct interactions with constituents of the replisome. However, the exact mechanisms of these interactions are not known, and it is unclear how tightly-bound gp32 filaments are readily displaced from ssDNA as required for genomic processing. Here, we utilized truncated gp32 variants to demonstrate a key role of the CTD in regulating gp32 dissociation. Using optical tweezers, we probed the binding and dissociation dynamics of CTD-truncated gp32, *I, to an 8.1 knt ssDNA molecule and compared these measurements with those for full-length gp32. The *I-ssDNA helical filament becomes progressively unwound with increased protein concentration but remains significantly more stable than that of full-length, wild-type gp32. Protein oversaturation, concomitant with filament unwinding, facilitates rapid dissociation of full-length gp32 from across the entire ssDNA segment. In contrast, *I primarily unbinds slowly from only the ends of the cooperative clusters, regardless of the protein density and degree of DNA unwinding. Our results suggest that the CTD may constrain the relative twist angle of proteins within the ssDNA filament such that upon critical unwinding the cooperative interprotein interactions largely vanish, facilitating prompt removal of gp32. We propose a model of CTD-mediated gp32 displacement via internal restructuring of its filament, providing a mechanism for rapid ssDNA clearing during genomic processing.

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Organophosphate poisoning is a common, under-reported cause of attempted and completed suicide worldwide. Following the resolution of the acute cholinergic syndrome, patients may develop respiratory muscle and proximal limb weakness, known as intermediate syndrome. A young man was brought to our rural hospital unconscious, in extremis, due to organophosphate pesticide poisoning. He developed atypical intermediate syndrome with global paralysis, persistent fasciculations and prolonged cholinergic symptoms, differing from the recognised presentation. He was intubated for fifteen days in our newly developed intensive care unit. Limited treatment options and the absence of blood gases, electrolyte testing, ECGs, invasive monitoring and imaging, in conjunction with regular disruptions to electricity and oxygen, and complications including seizures and pneumonia, all made this prolonged intubation an ambitious and challenging endeavour. We offer learning points for the acute physician and rural intensivist, and a summary of our reflections and hints for best care when adapting to a resource-limited setting.

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